The main goals of the experiments in this application are to evaluate the potential usefulness of transdominant negative (TD) rev proteins for anti-HIV therapy and to develop efficient vector systems for the delivery of TD rev and other genes. We propose to further study the capacity of different TD rev proteins to inhibit the replication of various molecular clones of HIV-I as well as of clinical isolates and chimeras. The efficacy of these approaches will be tested both in tissue culture systems and in the SCID-hu mouse model. He will also address the question of development of viral resistance to TD rev proteins. The specific aims of the application are: 1) To further evaluate different forms of TD rev proteins as a modality to achieve intracellular immunization against HIV-1 in cell culture. 2) To obtain and analyze virus variants that are resistant to the TD rev proteins. 3) To develop rev-independent packaging cell lines for replication-defective HIV-1 vectors expressing TD rev proteins. 4) To develop both replication defective and replication competent rev-independent HIV-1 vectors containing TD rev genes and study their properties in cell culture. 5) To study whether replication competent or defective HIV-1 variants carrying TD rev genes can protect thymocytes in the SCID-hu mouse from HIV-1 infection and pathogenesis.